Basic Oncology

DNA tumor viruses

 Features of viral carcinogenesis

Viral carcinogenesis is a multistep process

Viruses are seldom complete carcinogens (need cofactors)
Tumor viruses frequently establish persistent infections
Not all infections lead to tumor formation
Long time elapse between infection and tumor appearance
Viral markers (DNA, RNA) are usually present in tumor
Tumor viruses modulate growth control in cells
 DNA tumor viruses
DNA tumor viruses have transforming genes (viral oncogenes)
DNA virus oncogenes act by
 inactivating host tumor suppressor gene products (p53, pRB)
 or activation of host oncogenes
They influence the cell cycle and apoptosis

Two main parts of virus life cycle:

Early phase (early proteins: viral replication)
Late phase (late proteins: viral structural proteins, virion assembly)

Two types of virus life cycle:

Lytic (productive) cycle:
 Complete cycle, early and late genes expressed
 Virions produced, cell lysis (usually)
Latent cycle:
 Incomplete, only the early genes expressed
 No virions, cells survive for long
 Genetic changes may accumulate if oncogenes are present
 DNA tumor viruses

Virus family Virus Human cancer

Polyomaviridae SV40 (monkey) ?
JC, BK (human) ?

Papillomaviridae Human papillomaviruses Genital cancers

(HPV 16, 18, …) Other squamous cell
cancers
Herpesviridae EBV (Epstein-Barr virus) Burkitt’s lymphoma
Nasopharyngeal
carcinoma
B cell lymphoma
HHV-8 Kaposi’s sarcoma

Hepadnaviridae HBV (hepatitis B virus) Hepatocellular

carcinoma
Human papillomaviruses (HPV)

• >100 human papillomavirus (HPV) genotypes

• Small DNA tumor viruses (Family Papillomaviridae)
• Species-specific; epitheliotropic
• 55 nm dia non-enveloped capsid
• Circular dsDNA genome (~7,900 bp in length)
Papillomavirus
• Genome has 3 main functional coding regions; Virion

E genes (early viral function),

L genes (late viral function),
LCR (long control region) genes
• Genomic organization is highly conserved
LCR
 Clinical Significance of Representative HPV Types
>100 human papillomavirus (HPV) genotypes
 Cutaneous types - can lead to skin warts
 Mucosal types - different oncogenic potential
• High risk types (particularly 16 and 18)
– cervical cell abnormalities
– certain anogenital cancers
• Low risk types (particularly 6 and 11)
– usually resolve spontaneously and do not lead to cancer
– genital warts
– respiratory papillomatosis
Verruca vulgaris and plantaris
lesions - solitary or multiple
Rough-surfaced papules
exposed area
HPV-2
HPV-4
HPV-27
immune response slowly
Spontaneous regression
recurrence rate ↑
therapy (surgical
excision, lasertherapy,
cryotherapy, keratolytic
agents (salicilic acid)
Epidermodysplasia
verruciformis
HPV 5,8,9,12,14
first linkage (HPV-
epithelial cancer)
multiple atypical
exophytic verocous
lesions
may progress into
squamous cell
carcinoma
especially on sun-
exposed areas
Condyloma acuminatum

HPV 6,11
Transmission: sexual intercourse
Defined as exophytic verrucous lesions on
anogenital region
Recurrence rate ↑
Therapy – surgical excision, cryotherapy,
lasertherapy, keratolytic agents
 HPV and Genital Cancer
HPV 16, 18 are the most common HPVs can lead cervical leasions.

Normal Cx Mild Moderate Severe Invasive

Stratified squamous Dysplasia Dysplasia Dysplasia Disease
epithelium without atypia
(CIN I) (CIN II) (CIN III / CIS)
CIN: cervical intraepithelial neoplasia (premalignant lesion)
CIS: carcinoma in situ
 Normal Cervix High grade squamous intraepithelial lesion [HSIL]

Ordered basal Disrupted

Ordered Disrupted basal
epithelium differentiation
differentiation epithelium
 HPV E7 Can Promote Inappropriate
No Growth Signal E2F Entry Into the Cell Cycle

E2F
Rb Rb Growth Arrest
Rb

With Growth Signal

Rb
cdk/cyclin
E2F E2F Progression
Rb

No Growth Signal + E7
E2F E2F Progression
Rb

E7 E7
Rb
 Human Papillomavirus Vaccines
• Cervarix (bivalent vaccine)
• targets two HPV types: 16 and 18.

• Gardasil (quadrivalent vaccine)

protects against 4 HPV types: 6,11,16 and 18.
• prevents genital warts caused by HPV types 6 and 11.

• Both vaccines are also given in 3 doses over a 6 month

period.
• Althought HPV vaccines can help prevent future HPV
infection, they do not help eliminate existing HPV
infections.
 Epstein-Barr Virus (EBV)
• Belong to the gammaherpesvirus subfamily
of herpesviruses
• Nucleocapsid 100 nm in diameter
• Membrane is derived by budding through
nuclear membrane
• Genome is a linear double stranded DNA
molecule with 172 kbp
• The viral genome forms circular episomes
which reside in the nucleus.
 Pathogenesis
• Portal of entry is the nasopharynx, then virus infects
both B-cells and epithelial cells and establishes latent
infection
• EBV is able to immortalize B-lymphocytes in vitro
• EBV is associated with several very different diseases
where it may act directly or through one of several co-
factors.
Infectious Mononucleosis

www.lifemartini.com

Atypical lymphocytes
EBV infection
 Disease Association

1. Infectious Mononucleosis
2. Burkitt's lymphoma (Africa)
3. Nasopharyngeal carcinoma (China)
4. Lymphoproliferative disease and
B-cell lymphoma in the immunosuppressed.
 Burkitt’s Lymphoma
• Burkitt’s lymphoma (BL) is a rare type of B-cell
lymphoma
• The different types of BL are endemic and sporadic BL
• Burkitt's lymphoma occurs endemically in parts of Africa
and Papua New Guinea. It usually occurs in children and
young adults.
• It is restricted to areas with endemic malaria. Therefore
it appears that malaria infection is a cofactor.
• Multiple copies of EBV genome and some EBV antigens
can be found in BL cells and patients with BL have high
titres of antibodies against various EBV antigens.
• BL cells show a reciprocal translocation between the
long arm of chromosome 8 and chromosomes 14, 2 or 22.
Burkitt lymhoma
BL causes different
symptomes depending on
where in the body:
-Sore throat
-Difficulty swallowing
-Breathlessness
-Abdomen pain
-Diarrhoea

EBV is a common virus and

it is unknown why it may
increase the risk of
lymphoma in some people
but not others.
 Cancers often result from gene
Burkitt’s Lymphoma
translocations
8:14 translocation
Break in
chromosome 14 at
q32

myc

Acute myelocytic
leukemia
7:15
9:18
11:15:17
 Nasopharyngeal Carcinoma
• Nasopharyngeal carcinoma (NPC) is a malignant
tumor of the squamous epithelium of the
nasopharynx. It is very prevalent in China.
• Multiple copies of EBV genome and EBV
EBNA-1 antigen can be found in cells of
undifferentiated NPC. Patients with NPC have
high titres of antibodies against various EBV
antigens.
• Besides EBV there appears to be a number of
environmental and genetic cofactors in NPC.
Immunocompromised Patients

• Transplant recipients e.g. renal - EBV is

associated with the development of
lymphoproliferative disease and lymphoma.
• AIDS patients - EBV is associated with oral
leukoplakia and with various Non-Hodgkin’s
lymphoma.
 Human Herpes Virus 8
• Belong to the gammaherpesviruses subfamily of herpesviruses
• Originally isolated from cells of Kaposi’s sarcoma (KS) [other
name]
• HHV-8 DNA is found in almost 100% of cases of Kaposi’s
sarcoma
• Most patients with KS have antibodies against HHV-8
• Unlike other herpesviruses, HHV-8 does not have a ubiquitous
distribution.
• Variants of Kaposi’s sarcoma: - classic (in elderly men of eastern european origin)
- endemic (african children and adults)
- immunosuppression, transplantation-
associated
Kaposi’s Sarcoma
angioproliferative disorder

Skin lesions – various

(macules, papules, nodules)
(reddish, purplish blue)
with/without internal
involvement (GIT, lungs)
Nodular lesions may
ulcerate and bleed easily.
Hepatitis B Virus
 Hepatitis B Virus
Member of the Hepadnaviridae
Enveloped DNA virus:
partially ds DNA genome
Icosahedral symmetry (42 nm diameter
with envelope)
Envelope contains large amount of HBsAg

Encodes polymerase with RT (reverse

transcriptase) activity
Encodes X protein (trans-activating host
genes)

Transmission: parenteral (blood, sexual,

perinatal)

Chronic infection: continous productive

infection (virus is not directly cytolytic)
 Hepatitis B - Clinical Features
 Incubation period: Average 60-90 days
Range 45-180 days

 Acute viral hepatitis – an illness that begins with

general ill-health, loss of appetite, nausea, vomiting,
body aches, mild fever, and dark urine, and jaundice.

 Chronic hepatitis can be asymptomatic or leads

to cirrhosis over several years. This type of infection
dramatically increases the incidence of hepatocellular
carcinoma.
Spectrum of Chronic Hepatitis B Diseases

1. Chronic Persistent Hepatitis -

asymptomatic
2. Chronic active Hepatitis -
symptomatic exacerbations of hepatitis
3. Cirrhosis of Liver
4. Hepatocellular Carcinoma
 Cirrhosis and carcinoma
• Chronic infection is characterized
by the persistence of HBsAg for at
least 6 months Persistence of
HBsAg is the principal marker of risk
for developing chronic liver disease
and liver cancer (hepatocellular
carcinoma).
• scarring of liver
•leading to progressive loss of liver
function (decreased protein
production, detoxicating function
HBV remains a serious
global health problem.

HBV prevalence varies

enormously between
different countries.

There are 350 million

chronically infected
individuals.

HBV is responsible for 1,5

million deaths per year.
 HBV carcinogenesis
Two theories:

1. Indirect mechanism:
continous tissue damage and regeneration

2. Direct mechanism:
virus is oncogenic
HBV X protein trans-activates host oncogenes (myc)
Thank you for your attention!